Stroke causes death of brain tissue. The prevalence, and difficult recovery after brain injury make stroke one of the top causes of adult disability globally. Currently, therapies for stroke include clot removal within the first day after stroke in order to encourage reperfusion of brain blood vessels, however this is only viable for carefully selected patients. Even in instances of successful clot retrieval, half of these patients are still left with neurological deficits. Outside this limited window, neurorehabilitative practices are the most widely used therapies.
At first, stroke produces cell injury and death with obvious neurological impairments. However, weeks and months after the acute events of injury and death, there is extreme plasticity in brain circuits during the limited processes of recovery. Plasticity refers to the structural and/or functional changes within neurones that affect the connectivity of neurones with each other in a network with a specific function. These changes usually take place, for example, when learning or after injury, where there is a change in neuronal input or firing patterns induced by this input. These plasticity processes include turnover of local synaptic contacts next to the lesion, changes in excitability (the electrical properties of a neurone in response to a stimulus) of neuronal circuits that are next to and connected with the damaged brain area, and the formation of new functional neuronal connections, seen in remapping of motor, sensory, and language functions. Studies on post-stroke plasticity events have noted important principles governing the timing of these biological processes, and their role in the recovery of injured brain circuits, and most importantly, that these processes of recovery after acute brain injury are able to be manipulated; they can be controlled by drugs and brain stimulation protocols to enhance recovery in animal models.
Although this post will only lightly touch on very limited aspects of the paper in question, the original review itself focusses on the mechanisms of circuit changes and cortical plasticity after stroke, the shared mechanisms between memory formation and brain repair, the changes in neuronal excitability that underlie stroke recovery, and the molecular and pharmacological interventions that follow from these findings to promote motor recovery in animal models. However, this actual post itself will only focus on the circuit changes after stroke and how it can be enhanced to promote recovery.
There are four distinct time periods following stroke in which different cellular events take place; these are the hyperacute, acute, subacute and chronic phases (for more information and elaboration please see the original paper). Stroke induces a situation called a ‘transcriptional growth programme’, that encourages plasticity in the subacute phase. As a result of this transcriptional programme, over 500 different neuronal genes are distinctively regulated. Neurones in the main area of motor function recovery after stroke, the peri-infarct tissue (brain tissue that borders the site of damage), and its connected areas increase signalling pathways that encourage and support axon guidance (the neuronal axon’s transmits information to different neurones), growth factor responses, intracellular growth (such as increased production of adhesion molecules), and cytoskeletal rearrangement. These induced gene systems in neurones next to the site of damage/tissue loss, lead to axonal growth and synapse formation. Neurones in peri-infarct tissue have obvious new axonal projections that stretch by several millimetres into nearby key areas of the brain, including premotor, motor, sensory, and retrosplenial cortices, where most probably new functional synaptic connections are formed. Blocking these new connections stops stroke recovery in animal models. Connections between different regions of the brain are mostly brought about through excitatory synaptic contacts on dendritic spines (sites on the neurone that receive synaptic inputs). In the subacute phase of stroke, there is increased dendritic spine turnover, therefore giving rise to the synaptic termination of new connections.
One main means of reduced neuronal excitability following stroke comes from increases in inhibitory neurotransmitter signalling, such as signalling that uses GABA (a chemical messenger in the brain) in tissues next to the site of damage. GABAergic signalling produces tonic (slow) and persistent inhibition. This inhibition is known as the shunt current, and it establishes the threshold for action in neurones such as those called pyramidal neurones. Stroke causes accumulation of GABA, and so in the peri-infarct brain following stroke, tonic GABAergic signalling is increased in the initial weeks, producing slow and persistent inhibition. Blocking the GABAAR α5 subunit (which is a structural part of GABA receptors) following stroke, either genetically or pharmacologically, results in the restoration of pyramidal neurone excitability and boosts functional recovery. Therefore, reducing tonic inhibition promotes recovery.
As well as methods that block the increase of inhibitory signalling following stroke, the enhancement of excitatory signalling in the tissue next to the site of damage can aid recovery. Treatment with positive modulators of AMPA-type glutamate receptors (AMPARs), known as AMPAkines, assists AMPAR signalling. Glutamate binding to AMPARs causes entry of positive ions, increased excitation, and downstream gene expression, such as the expression of brain-derived neurotrophic factor (BDNF; a protein essential for cognitive function). AMPAkines encourage motor function recovery in stroke by selectively boosting BDNF signalling in the peri-infarct motor cortex. A different approach to boosting AMPAR signalling, which leads to increased AMPAR levels at postsynaptic sites, also enhances motor recovery following stroke. This effect is mediated through a protein called CRMP2, which pushes increased numbers of AMPARs to the cell surface and improves recovery following brain lesions.
These findings involving GABAergic and glutamatergic signalling indicate that enhancing neuronal excitability following stroke in very selective ways promotes recovery in rodent models of disease. However, this recovery is only enhanced in the subacute period following stroke.
As mentioned earlier, this blog post hasn’t touched on all aspects of the review, so for more information and for the full story, I highly recommend reading the original paper. It’s a great read.
Original Paper: Joy, M.T. and Carmichael, S.T. (2021) “Encouraging an excitable brain state: mechanisms of brain repair in stroke.” Nature Reviews Neuroscience. doi.org/10.1038/s41583-020-00396-7
Original Link: https://www.nature.com/articles/s41583-020-00396-7
Featured Image: OASH, Stroke Symptoms. Women’s Health. https://www.womenshealth.gov/heart-disease-and-stroke/stroke/stroke-symptoms
Edited by Cyrus Rohani-Shukla